Ischemia is a major cause of cell injury in human disease. The ravages of atherosclerosis on the brain, heart, kidneys, bowels, and legs are mediated by its consequent ischemia. Such a central role for ischemia necessitates a detailed knowledge of the biochemical mechanisms underlying its effects on cells. Based on the previous work of others, recent studies by the Principal Investigator have revealed what is the likely nature of the major biochemical event underlying the reaction of cells to ischemia that results in irreversible cell injury. The first objective of the research proposed below is to understand the mechanisms responsible for an accelerated degradation of phospholipid in ischemic cells. Evidence has also been obtained that the mitochondrial alterations in ischemia are unlikely to be casually related to the loss of reversibility. The second objective is to further substantiate this conclusion. Finally, as an initial approach to the therapeutic manipulation of ischemic cells, it is proposed to modify membrane phospholipids by varying the polar head groups and the fatty acid content with the expectation of altering the reaction to ischemia.